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Functional Genomics to Inform Gene Environment Interactions

Principal Investigator
Name
Ulrike Peters
Degrees
Ph.D, M.P.H
Institution
Fred Hutchinson Cancer Center
Position Title
Associate Director, Public Health Sciences
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
PLCO-310
Initial CDAS Request Approval
Oct 12, 2017
Title
Functional Genomics to Inform Gene Environment Interactions
Summary
Colorectal cancer (CRC) is a complex disease with both genetic (G) and environmental (E) risk factors contributing to susceptibility. Genome-wide GxE interaction scans (GWIS) can help identify novel susceptibility loci and biologically meaningful GxE interactions that point to new carcinogenic mechanisms. Limited statistical power remains a primary concern in GxE analyses. To maximize the statistical power in a GWIS, it is essential to have the largest possible sample size by pooling resources across studies. In this project, we will combine the resources of three existing CRC consortia (approximately 53,600 cases and 52,400 controls of European descent): the Colorectal Cancer Family Registry (CCFR), the Colorectal Cancer Transdisciplinary (CORECT) Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) for interaction testing with 8 environmental and lifestyle factors: alcohol, calcium, folate, hormone replacement therapy (HRT), non- steroidal anti-inflammatory drugs (NSAIDs), red meat, processed meat, and smoking. We would like to include PLCO GWAS and epidemiologic data that are already a part of GECCO as part of this project.
Aims

Aim 1. Build colorectal (CR)- and environmental (E)-specific functional weights for single variants
and gene sets across the genome to inform Aim 2. Functional genomic weights will be derived using
CR enhancer/promoter profiles (based on ChIPseq and DHS) from Roadmap85 and our own experiments in normal colon tissue, in combination with our own E-specific gene expression in 250 normal colon biopsies, as well as 50 colon 3D organoids. These data will also be used to link enhancers to gene targets providing biologically meaningful gene sets for aggregate testing of rare variants given that statistical power is limited to test these individually.

Aim 2. Discover novel GxE interactions for CRC for rare and common genetic variants (down to minor allele frequency of 0.1%) in up to 53,600 cases and 52,442 controls of European descent. Using novel statistical methods that will incorporate the CR- and E-specific functional weights (Aim 1), we will conduct GWIS for eight environmental factors: alcohol, calcium, folate, hormone replacement therapy (HRT), non-steroidal anti-inflammatory drugs (NSAIDs), red meat, processed meat, and smoking. To narrow in on likely causal variant(s) from novel interactions, we will conduct trans-ethnic fine-mapping
analyses including 23,516 participants of African, Asian and Hispanic descent.

Aim 3. To validate functional/causal variants of GxE interactions and their gene targets. Using novel findings from Aim 2, as well as previously identified novel GxE, we will (1) validate functional variants in enhancer-gene links using site directed mutagenesis and in vitro luciferase enhancer activity assays; (2) validate/identify candidate target genes following knock-down of candidate enhancers in CRC cell lines by CRISPR-Cas9 genome editing; and (3) validate GxE interactions in human 3D colon organoids (“mini guts”) exposed to environmental E.

Collaborators

Michael Bassik (Stanford University)
Graham Casey (University of Virginia)
David Conti (University of Southern California)
Jim Gauderman (University of Southern California)
Anshul Kundaje (Stanford University)
Loic LeMarchand (University of Hawaii)
Victor Moreno (IDIBELL)
John Morrison (University of Southern California)
Peter Scacheri (Case Western)
Steve Gruber (University of Southern California)